The present invention relates to a novel compound which is useful as a prodrug, a pharmaceutical composition containing the same and an intermediate therefor. More particularly, the present invention relates to a novel tricyclic compound having an acyloxymethoxycarbonyl side chain, an immunosuppressant and an antiallergic agent containing the same as well as a novel tricyclic compound having the immunosuppressive activity and the antiallergic activity and an intermediate therefor.
Making of prodrugs for pharmaceutical active substances is studied in many cases for the purpose of improving the physical properties such as the crystallizability, the stability, the water-solubility and the like, the bioavailability, and duration of the pharmacological activity. In particular, although it is desirable to convert amine compounds into a prodrug for the purpose of enhancing the absorbability and the stability, simple amidated prodrugs can not be returned to amines in the living body and it is said that procedures for converting into a prodrug require elaboration.
In WO97/39999 and WO98/04508, it is disclosed that para-terphenyl derivatives are effective as an immunosuppressant and an antiallergic agent. In particular, WO98/04508 refers to prodrugs and, more particularly, describes conversion of hydroxy compounds into a prodrug.
In JP-A23359/1985, JP-A18747/1986 and WO96/18605, described is a method of making a prodrug by substituting primary or secondary amines with xe2x80x94COOCR1R2OCOR3 (R3=alkyl, carboxyalkyl, haloalkyl, carbamylalkyl etc.). In addition, in JP-A503925/1993 and Synthesis (December, 1990, 1159-1166), there are described R2SCOOCH2OCOR1 (Compound A) and ClCOOCH2OCOR1 (Compound B) as an intermediate for synthesizing a prodrug. However, it is clearly described therein that Compound B can not be synthesized from Compound A (wherein R1 is hydroxyethyl or acetylaminomethyl, and R2 is ethyl) according to those methods.
Compounds having the similar skeleton to that of the present compound and having the immunosuppressive activity or the antiallergic activity are described in WO94/27980, WO95/13067, WO96/15123, WO95/15318, WO96/40659, WO96/40143, WO96/38412, WO96/10012, WO97/24356, WO97/27181, WO97/24324, WO97/44333, WO97/46524, WO98/04508, WO98/24766, WO98/24782, WO98/56785, FR2301250, U.S. Pat. No. 5,593,991, JP-B7368/1972, JP-A91259/1976, JP-A3163/1996, JP-A124571/1997, JP-A71564/1997, JP-A124571/1997, JP-A79993/1999, Bioorganic and Medicinal Chemistry Letters, Vol.5, No.18, p2143-2146(1995), J. Med. Chem., 1974, Vol.17, NO.11, 1177-1181 and the like.
Additionally, liquid crystalline compounds having the similar skeleton to that of the present compound are disclosed in JP-A121225/1983, JP-A87253/1997, JP-A253065/1988, JP-A106864/1986, JP-A106871/1986, JP-A83346/1990, JP-A48760/1997, JP-A31063/1997, WO88/07992 and the like, compounds having the insecticidal or miticidal activity in JP-A193067/1996, compounds having the circulatory disease and psychosis-treating activity in EP0600717A1, and compounds having the central nervous disease-treating activity in WO95/15954.
An object of the present invention is to provide a novel prodrug of a compound having the immunosuppressive activity and/or the antiallergic activity.
The present invention provides the following compounds or pharmaceutically acceptable salts thereof or prodrugs thereof.
[1] A compound represented by the formula (I): 
(hereinafter, referred to as compound (I))
wherein one of X and Xxe2x80x2 is xe2x80x94N(COOCR3R2OCOR1)xe2x80x94, the other is xe2x80x94(CH2)s- (wherein s is an integer of 0 to 2), xe2x80x94Oxe2x80x94, xe2x80x94NRAxe2x80x94 (wherein RA is hydrogen, optionally substituted lower alkyl, lower alkenyl or lower alkylcarbonyl), xe2x80x94N(COOCR3R2OCOR1)xe2x80x94 or xe2x80x94S(O)p- (wherein p is an integer of 0 to 2),
R1 is lower alkyl substituted with 1 or 2 groups selected from the group consisting of xe2x80x94CONH2, xe2x80x94CONHCH3, xe2x80x94CONHC2H5, xe2x80x94OCONH2, xe2x80x94OCONHCH3, xe2x80x94OCONHC2H5, xe2x80x94(NHCOCRRxe2x80x2)mNHCOCH3, xe2x80x94(NHCOCRRxe2x80x2)mNHCOC2H5, xe2x80x94CSNH2, xe2x80x94(OCH2CH2)nOH, xe2x80x94OCH3, xe2x80x94(OCH2CH2)nOCH3, xe2x80x94COCH3, xe2x80x94COC2H5, xe2x80x94OCOCH3, xe2x80x94OCOC2H5, xe2x80x94NHOH, xe2x80x94NHCONH2, xe2x80x94NHCSNH2, xe2x80x94NHSO2CH3, xe2x80x94N(SO2CH3)2, xe2x80x94O2NH2, xe2x80x94SOCH3, xe2x80x94SO2CH3, xe2x80x94OCH2CONH2, xe2x80x94OCH2CON(CH3)2, xe2x80x94SO2N(CH3)2, xe2x80x94PO(OCH3)2, xe2x80x94NHCSNHC2H5, xe2x80x94CHxe2x95x90NNHCONH2, xe2x80x94CHxe2x95x90NNHCSNH2, xe2x80x94CHxe2x95x90NNHSO2CH3, triazolyl and tetrazolyl (wherein R and Rxe2x80x2 are each independently hydrogen or lower alkyl, m is an integer of 0 to 2, and n is an integer of 1 or 2),
R2 and R3 are each independently hydrogen or lower alkyl,
Y and Yxe2x80x2 are each independently hydrogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted lower alkoxycarbonyl, optionally substituted sulfamoyl, optionally substituted amino, optionally substituted aryl or optionally substituted 5-membered or 6-membered heterocycle,
when X is xe2x80x94CH2xe2x80x94, Y may be optionally substituted lower alkoxy,
when Xxe2x80x2 is xe2x80x94CH2xe2x80x94, Yxe2x80x2 may be optionally substituted lower alkoxy,
when X is xe2x80x94Oxe2x80x94 or xe2x80x94NRAxe2x80x94, Y may be optionally substituted lower alkylsulfonyl or optionally substituted arylsulfonyl,
when Xxe2x80x2 is xe2x80x94Oxe2x80x94 or xe2x80x94NRAxe2x80x94, Yxe2x80x2 may be optionally substituted lower alkylsulfonyl or optionally substituted arylsulfonyl,
ring A, ring B and ring C are each independently optionally substituted aromatic carbocycle or optionally substituted 5-membered or 6-membered heterocycle which may be fused with a benzene ring,
when ring A, ring B and/or ring C are optionally substituted 5-membered-heterocycle, W1, W2 and/or W3 represent a bond,
one of V1 and V2 is a single bond, the other is a single bond, xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94OCH2xe2x80x94, xe2x80x94CH2Oxe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94CH(ORB)xe2x80x94 (wherein RB is hydrogen or lower alkyl), xe2x80x94COxe2x80x94, xe2x80x94NHCHRCxe2x80x94 or xe2x80x94CHRCNHxe2x80x94 (wherein RC is hydrogen or hydroxy),
when both V1 and V2 are a single bond, at least one of ring A, ring B and ring C is optionally substituted aromatic carbocycle, and at least one is optionally substituted 5-membered or 6-membered heterocycle which may be fused with a benzene ring,
[2] a compound represented by the formula (II): 
(hereinafter, referred to as compound (II))
wherein one of X and Xxe2x80x2 is xe2x80x94N(COOCR3R2OCOR1)xe2x80x94, and the other is xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94 or xe2x80x94N(COOCR3R2OCOR1)xe2x80x94,
Y and Yxe2x80x2 are each independently optionally substituted lower alkyl, optionally substituted lower alkenyl or optionally substituted lower alkynyl,
R1, R2 and R3 have the same meanings as those for [1],
ring A and ring C are each independently optionally substituted benzene ring or optionally substituted 6-membered heterocycle containing 1 or 2 heteroatoms, at least one of them being 6-membered heterocycle,
R8, R9, R10 and R11 are each independently hydrogen, halogen, hydroxy, optionally substituted lower alkyl, optionally substituted lower alkoxy, optionally substituted lower alkenyl, optionally substituted lower alkenyloxy, optionally substituted cycloalkyloxy, optionally substituted acyloxy, carboxy, optionally substituted lower alkoxycarbonyl, optionally substituted lower alkenyloxycarbonyl, optionally substituted lower alkylthio, optionally substituted lower alkenylthio, optionally substituted amino, optionally substituted carbamoyl, guanidino, nitro, optionally substituted lower alkylsulfonyl, optionally substituted lower alkylsulfonyloxy, optionally substituted arylsulfonyl or optionally substituted arylsulfonyloxy,
[3] a compound represented by the formula (III): 
(hereinafter, referred to as compound (III))
wherein X is xe2x80x94NHxe2x80x94 or xe2x80x94N(COOCR3R2OCOR1)xe2x80x94, Xxe2x80x2 is xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94 or xe2x80x94N(COOCR3R2OCOR1)xe2x80x94, at least one of X and Xxe2x80x2 being xe2x80x94N(COOCR3R2OCOR1)xe2x80x94,
Y and Yxe2x80x2 are each independently optionally substituted lower alkyl or optionally substituted lower alkenyl,
R1, R2 and R3 have the same meanings as those for [1],
R4, R5, R6, R7, R8, R9, R10 and R11 are each independently hydrogen, halogen, hydroxy, optionally substituted lower alkyl, optionally substituted lower alkoxy, optionally substituted lower alkenyl, optionally substituted lower alkenyloxy, carboxy, optionally substituted lower alkoxycarbonyl or optionally substituted amino,
ring C is pyridine or pyrimidine, each being optionally substituted with lower alkyl,
[4] a compound described in any one of [1] to [3], wherein R1 is C1 to C3 alkyl substituted with 1 or 2 groups selected from the group consisting of xe2x80x94CONH2, xe2x80x94OCONH2 and xe2x80x94(NHCOCRRxe2x80x2)mNHCOCH3,
[5] a compound described in [3], wherein R4 and R5 are each independently hydrogen or halogen,
[6] a compound described in [3], wherein R6 and R7 are both hydrogen,
[7] a compound described in [2] or [3], wherein R8 and R11 are each independently hydrogen, hydroxy or lower alkyl,
[8] a compound described in [2] or [3], wherein R9 and R10 are each independently lower alkyl, lower alkoxy or lower alkoxycarbonyl,
[9] a compound described in any one of [1] to [3], wherein Xxe2x80x2 is xe2x80x94Oxe2x80x94,
[10] a compound described in [3], wherein X is xe2x80x94NHxe2x80x94 or xe2x80x94N(COOCR3R2OCOR1)xe2x80x94, Xxe2x80x2 is xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94 or xe2x80x94N(COOCR3R2OCOR1)xe2x80x94, at least one of X and Xxe2x80x2 being xe2x80x94N(COOCR3R2OCOR1)xe2x80x94,
R1 is C1 to C3 alkyl substituted with 1 or 2 groups selected from the group consisting of xe2x80x94CONH2, xe2x80x94OCONH2 and xe2x80x94(NHCOCRRxe2x80x2)mNHCOCH3, R2 and R3 are hydrogen or C1 to C3 alkyl,
Y and Yxe2x80x2 are each independently lower alkyl optionally substituted with halogen or lower alkenyl optionally substituted with halogen, R4 and R5 are each independently hydrogen or halogen, R6 and R7 are both hydrogen, R8 and R11 are each independently hydrogen, hydroxy or lower alkyl, R9 and R10 are each independently lower alkyl, lower alkoxy or lower alkoxycarbonyl, and ring C is pyridine or pyrimidine, each being optionally substituted with lower alkyl,
[11] a compound described in any one of [1], [2], [3] and [10], wherein Y and Yxe2x80x2 are both prenyl,
[12] a compound described in [3] or [4], wherein ring C is 
R4and R5 are each independently hydrogen, halogen or lower alkoxy, R6 and R7 are each independently hydrogen, halogen or lower alkyl, R8 and R11 are both lower alkyl, or one of them is lower alkyl and the other is hydrogen or lower alkoxy, R9 and R10 are both hydrogen, lower alkyl or lower alkoxy, and one of xe2x80x94Xxe2x80x94Y and xe2x80x94Xxe2x80x2xe2x80x94Yxe2x80x2 is xe2x80x94N(COOCR3R2OCOR1)-(optionally substituted lower alkyl or optionally substituted lower alkenyl), and the other is prenyloxy or prenylamino,
[13] a compound described in [3] or [4], wherein ring C is 
wherein X has the same meaning as that for [3], a salt or solvate thereof.
Another embodiment of the present invention provides a pharmaceutical composition containing a compound described in any one of [1] to [13] or a pharmaceutically acceptable salt or solvate thereof, more particularly, an immunosuppressive agent or an antiallergic agent. Furthermore, the present invention provides a method for inhibiting an immunoreaction, or a method for treating or preventing allergic diseases, which comprises administering a compound (I). Further, the present invention provides use of a compound for preparing a medicament for inhibiting an immunoreaction, or treating or preventing allergic diseases.
Another embodiment of the present invention provides the following compounds useful as an intermediate for compounds (I) and (II):
a compound represented by the formula (VIIbxe2x80x2): 
wherein one of R4 and R5 is hydrogen, the other is halogen, R8 and R11 are each independently hydrogen, hydroxy or lower alkyl, R9 and R10 are each independently lower alkyl, lower alkoxy or lower alkoxycarbonyl, Lxe2x80x2 is dihydroxyboryl, di-lower alkylboryl or di-lower alkoxyboryl, a pharmaceutically acceptable salt or solvate thereof, and
a compound represented by the formula (VIbxe2x80x2): 
wherein ring C is pyridine ring optionally substituted with lower alkyl or pyrimidine ring optionally substituted with lower alkyl, T is protected hydroxy, lower alkylthio or arylthio, Zxe2x80x2 is dihydroxyboryl, di-lower alkylboryl or di-lower alkoxyboryl, and s is an integer of 0 to 2, or pharmaceutically acceptable salt or solvate thereof.